ENZYMATIC MECHANISMS OF THYROXINE*

Abstract

THE general metabolic effects following the removal of the thyroid gland and replacement therapy by thyroxine are well known and firmly established by many observations on patients and experiments in animals. However, the actual site of action of thyroxine in metabolic exchange in cells is obscure. Barker (1) in his recent review on thyroid mechanisms states that no in vitro response to thyroxine has been obtained which gives consistent enough results to be used as a means of testing further the mechanisms of the action of thyroxine. It was in this unsatisfactory state of knowledge that this present work was started. Several actions of thyroxine on oxidative systems have been described (2, 3) and a hypothesis has been formulated for thyroxine action for future work. The first positive experiment on an enzyme system with thyroxine was derived from a study (2) of the action of this hormone on ascorbic acid oxidase, a copper enzyme from a plant source. Thyroxine stimulated the uptake of oxygen in the ascorbic acid-ascorbic acid oxidase system. This effect was obtained by concentrations of thyroxine as low as 0.9 × 10−⁶ M. The explanation for this effect was given in terms of a free radical (semiquinone) formation of thyroxine (3). It was postulated that during the course of the oxidation of ascorbic acid, the semiquinone of thyroxine was formed, which could oxidize a molecule of ascorbic acid with the reformation of thyroxine. Huszák (4) postulated a similar mechanism for the stimulatory action of flavonoids on this system. This idea suggests that thyroxine forms a reversible oxidation-reduction system through the action of an oxidase, and, therefore, aids oxidation in this manner. The suggestion that thyroxine can form such a system is not new. For example, Niemann and his associates (5, 6) tested several isomers of thyroxine and found that only the ones which could form a quinoid form had the ability to raise the metabolism of rats. The others, incapable of this mechanism on account of the position of the hydroxyl group, were not active. Therefore, they concluded from these experiments that thyroxine worked through an oxidation-reduction mechanism.